Author:
Hu Jing,Gao Chen,Wei Chaoliang,Xue Yuanchao,Shao Changwei,Hao Yajing,Gou Lan-Tao,Zhou Yu,Zhang Jianlin,Ren Shuxun,Chen Ju,Wang Yibin,Fu Xiang-Dong
Abstract
Heart performance relies on highly coordinated excitation–contraction (EC) coupling, and defects in this critical process may be exacerbated by additional genetic defects and/or environmental insults to cause eventual heart failure. Here we report a regulatory pathway consisting of the RNA binding protein RBFox2, a stress-induced microRNA miR-34a, and the essential EC coupler JPH2. In this pathway, initial cardiac defects diminish RBFox2 expression, which induces transcriptional repression of miR-34a, and elevated miR-34a targetsJph2to impair EC coupling, which further manifests heart dysfunction, leading to progressive heart failure. The key contribution of miR-34a to this process is further established by administrating its mimic, which is sufficient to induce cardiac defects, and by using its antagomir to alleviate RBFox2 depletion-induced heart dysfunction. These findings elucidate a potential feed-forward mechanism to account for a critical transition to cardiac decompensation and suggest a potential therapeutic avenue against heart failure.
Publisher
Proceedings of the National Academy of Sciences
Cited by
30 articles.
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